Endovascular Valve Edge-to-Edge
REpair Study (EVEREST II)
Randomized Clinical Trial:
Primary Safety and Efficacy Endpoints
Ted Feldman, Laura Mauri, Elyse Foster, Don Glower on
behalf of the EVEREST II Investigators
American College of Cardiology
March 14, 2010
Atlanta, GA
Disclosures
 Research Grants – Abbott, Edwards
 Consultant – Abbott, Edwards
2
Investigational Device only in the US; Not available for sale in the US
Perspective
 >250,000 cases of significant Mitral Regurgitation
diagnosed annually in the US
 Current therapeutic options:
• Medical management
– Effective in symptom management
– Ineffective in treating underlying pathophysiology or disease
progression
• Surgical Repair or Replacement (Standard of Care)
– Effective yet invasive with associated morbidity
– Only ~20% of patients with significant MR undergo MV surgery
 Unmet need for an effective less invasive option
3
Investigational Device only in the US; Not available for sale in the US
Catheter-Based Mitral Valve Repair
MitraClip® System
4
Investigational Device only in the US; Not available for sale in the US
Clinical Experience
Study
Population
n
EVEREST I (Feasibility)*
Non-randomized
55
EVEREST II*
Pre-randomization
60
EVEREST II
High Risk Registry
78
EVEREST II (Pivotal)
Randomized patients
(2:1 MitraClip to Surgery)
279
REALISM (Continued Access)
High Risk & Non High Risk
European Experience
184 MitraClip
95 Surgery
266
472
Total
1,115
MitraClip
*Percutaneous Mitral Valve Repair Using the Edge-to-Edge Repair: Six months Results of the EVEREST Phase I Clinical trial, JACC 2005;46:2134-2140.
Percutaneous Mitral Repair with the MitraClip System: Safety and Midterm Durability in the Initial EVEREST Cohort, JACC 2009; 54:686-694.
Data as of 2/15/2010.
Investigational Device only in the US; Not available for sale in the US
5
EVEREST II Randomized Clinical Trial
Study Design
279 Patients enrolled at 37 sites
Significant MR (3+-4+)
Specific Anatomical Criteria
Randomized 2:1
Device Group
MitraClip System
N=184
Control Group
Surgical Repair or Replacement
N=95
Echocardiography Core Lab and Clinical Follow-Up:
Baseline, 30 days, 6 months, 1 year, 18 months, and
annually through 5 years
6
Investigational Device only in the US; Not available for sale in the US
EVEREST II Randomized Clinical Trial
Study Organization
Principal Investigators:
Ted Feldman, MD
Evanston NorthShore University HealthSystem
Donald Glower, MD
Duke University Medical Center
Academic Research Organization:
Laura Mauri, MD
Harvard Clinical Research Institute
Data Safety Monitoring Board:
Richard Shemin, MD
University of California, Los Angeles
Clinical Events Committee:
Don Cutlip, MD
Echocardiography Core Lab:
Elyse Foster, MD
Sponsor:
Abbott Vascular Structural Heart (Evalve)
Harvard Clinical Research Institute
University of California, San Francisco
Menlo Park, CA
7
Investigational Device only in the US; Not available for sale in the US
EVEREST Clinical Investigators
T Feldman, J Alexander, R Curran, E Chedrawy, S Smart, M Lampert
A Wang, D Glower, J Jollis
T Byrne, P Tibi, HK Fang, JM Morgan
R Quesada, J Lamelas, N Moreno, R Machado
P Grayburn, B Hamman, R Hebeler, M Mack, W Ryan
A Eisenhauer, M Davidson, L Cohn, J Wu
J Hermiller, D Heimansohn, K Allen, D Segar
M Rinaldi, E Skipper, R Steigel, J Cook, G Rose
S Kar, G Fontana, A Trento, R Kass, W Cheng, R Siegel, K Tolstrup
P Whitlow, T Mihaljevic, N Smidera, L Sevensson, E Roselli, L Rodriquez, W Stewart
H Wasserman, W Gray, A Stewart, M Williams, M Argenziano, S Homma, R Pizzarello, L Gillam
P Block, Z Ghazzal, T Vassiliades, R Martin, J Merlino, S Lerakis
B Whisenant, S Clayson, B Reid, S Horton, J Orford
R Smalling, G Letsou, J Walkes, C Loghin
W Pedersen, V Kshettry, F Eales, T Flavin, T Kroshus, R Bae
O Nass, D Gangahar, R Jex, R Kacere
SC Wong, OW Isom, L Girardi, K Krieger, R Devereux, R Mishra
J Slater, A Galloway, G Perk, I Kronzon
S Ramee, C Van Meter, P Parrino, C Lavie, Y Gilliland, VS Lucas
R Kipperman, S Lucas, RM Bodenhamer, J Randolph, J Williams
R Leung, R MacArthur, J Mullen, D Ross, J Choy
P Kramer, B Castlemain, A Schwartz, L Crouse, V Pasnoori
A Berke, N Robinson, R Colangelo, P Damus, H Fernandez, J Taylor, N Bercow, A Katz
M O'Donnell, M Qureshi, A Pruitt, B Kong, B McAllister, S Girard
T Bajwa, D O’Hair, D Kress, K Sagar
JT Maddux, M Sanz, S Tahta, JM Maxwell, B Berry, J Knapp
W Gray, M Reisman, W Curtis, D Gartman, J Teply, D Warth, K Krabill
P Fail, K Paape, T Fudge, M Trotter, M Allam, E Feinberg, V Tedesco, D Solet
E Horlick, T David, M Borger, M Mezody
R Low, N Young, K Shankar, R Calhoun, W Bommer
J Carroll, J Cleveland, R Quaife
H Herrmann, M Acker, YJ Woo, F Silvestry, S Wiegers
S Bailey, E Sako, J Erikson
DS Lim, I Kron, J Kern, J Dent, H Gutgesell
E Fretz, J Ofiesh, M Mann
K Kent, S Boyce. P Sears-Rogan
J Lasala, M Moon, R Damiano, B Lindman, A Zajarias, J Madrazo
G Hanzel, F Shannon, M Sakwa, A Abbas, M Gallagher, P Markovitz
NorthShore University HealthSystem, Evanston, IL
Duke University, Durham, NC
Banner Good Samaritan Medical Center, Phoenix, AZ
Baptist Hospital of Miami, Miami, FL
Baylor University Medical Center, Dallas, TX
Brigham and Women’s Hospital, Boston, MA
The Care Group, Indianapolis, IN
Carolinas Medical Center, Charlotte, NC
Cedars-Sinai Medical Center, Los Angeles, CA
The Cleveland Clinic, Cleveland, OH
Columbia University, New York, NY; Danville, CT
Emory University Hospital, Atlanta, GA
Latter Day Saints Hospital, Salt Lake City, UT
Memorial Hermann Hospital, Houston, TX
Minneapolis Heart Institute, Minneapolis, MN
Nebraska Heart Institute, Lincoln, NE
New York Presbyterian Hospital, New York, NY
NYU Medical Center, New York, NY
Ochsner Clinic Foundation, New Orleans, LA
Oklahoma Heart Hospital, Okalahoma City, OK
Royal Alexandra Hospital, Edmonton, AB, Canada
Shawnee Mission Medical Center, Shawnee Mission, KS
St. Francis Hospital, Long Island, NY
St. Joseph’s Mercy Hospital, Ypsilanti, MI
St. Luke’s Medical Center, Milwaukee, WI
St. Patrick's Hospital & Health Science Ctr, Missoula, MT
Swedish Medical Center, Seattle, WA
Terrebonne General Medical Center, Houma, LA
Toronto General Hospital, Toronto, ON, Canada
University of California at Davis, Sacramento, CA
University of Colorado Health Sciences Center, Denver, CO
University of Pennsylvania, Philadelphia, PA
University of Texas Health Sciences Ctr, San Antonio, TX
University of Virginia, Charlottesville, VA
Victoria Heart Institute Foundation, Victoria BC, Canada
Washington Hospital Center, Washington DC
Washington University Medical Center, St. Louis, MO
William Beaumont Hospital, Royal Oak, MI
Interventional Cardiologist, Cardiac Surgeon, Echocardiologist
Investigational Device only in the US; Not available for sale in the US
8
EVEREST II Randomized Clinical Trial
Key Inclusion/Exclusion Criteria
Exclusion
Inclusion
• Candidate for MV Surgery
• Moderate to severe (3+) or
severe (4+) MR
– Symptomatic
– Creatinine >2.5mg/dl
o >25% EF & LVESD ≤55mm
– Asymptomatic with one or
more of the following
o
o
o
o
LVEF 25-60%
LVESD ≥40mm
New onset atrial fibrillation
Pulmonary hypertension
ACC/AHA Guidelines
JACC 52:e1-e142, 2008
• AMI within 12 weeks
• Need for other cardiac surgery
• Renal insufficiency
• Endocarditis
• Rheumatic heart disease
• MV anatomical exclusions
– Mitral valve area <4.0cm2
– Leaflet flail width (≥15mm)
and gap (≥10mm)
– Leaflet tethering/coaptation
depth (>11mm) and length
(<2mm)
9
Investigational Device only in the US; Not available for sale in the US
EVEREST II Randomized Clinical Trial
Baseline Demographics & Co-morbidities
Age (mean)
Male
Congestive heart failure
Coronary artery disease
Myocardial infarction
Angina
Atrial fibrillation
Cerebrovascular disease
Peripheral vascular disease
Cardiomyopathy
Hypercholesterolemia
Hypertension
Moderate to severe renal disease
Diabetes
Previous cardiovascular surgery
MR Severity: 3+ to 4+
MR Etiology: Degenerative / Functional
Device (%)
Control (%)
n=184
n=95
P
67.3 years
62.5
90.8
47.0
21.9
31.9
33.7
7.6
6.5
17.9
61.0
72.3
3.3
7.6
22.3
95.7
73 / 27
65.7 years
66.3
77.9
46.3
21.3
22.2
39.3
5.3
11.6
14.7
62.8
78.9
2.1
10.5
18.9
92.6
73 / 27
0.32
0.60
<0.01
>0.99
>0.99
0.12
0.42
0.62
0.17
0.61
0.80
0.25
0.72
0.50
0.54
0.48
0.81
10
Investigational Device only in the US; Not available for sale in the US
EVEREST II Randomized Clinical Trial
Demographic Comparison
EVEREST II
RCT
2008 STS Database
Isolated 1st Elective
Operation for MR*
n=279
Repair
Replace
High Volume Hospitals
(>140/Yr)
Age yrs (mean)
68
60
61
59
≥65 yrs
58%
37%
45%
n/a
≥75 yrs
32%
n/a
n/a
0%
NYHA Class III or IV
50%
26%
45%
n/a
CHF
86%
41%
58%
n/a
Hypertension
75%
60%
67%
43%
Diabetes Mellitus
9%
13%
23%
6.5%
COPD / Chronic Lung
Disease
15%
17%
29%
n/a
EF (mean)
60%
53%
55%
56%
*Gammie JS et al Influence of Hospital Procedural Volume on Care Process and Mortality for Patients Undergoing Elective
Surgery for Mitral Regurgitation. Circ 2007;115:881-887.
Investigational Device only in the US; Not available for sale in the US
11
EVEREST II Randomized Clinical Trial
Primary Endpoints
Safety
 Major Adverse Event Rate at 30 days
 Per protocol cohort
 Superiority hypothesis
Effectiveness
 Clinical Success Rate
Pre-Specified MAEs
Death
Major Stroke
Re-operation of Mitral Valve
Urgent / Emergent CV Surgery
Myocardial Infarction
Renal Failure
Deep Wound Infection
Ventilation >48 hrs
New Onset Permanent Atrial Fib
Septicemia
GI Complication Requiring Surgery
All Transfusions ≥2 units
• Freedom from the combined outcome of
– Death
– MV surgery or re-operation for MV dysfunction
– MR >2+ at 12 months
 Per protocol cohort
 Non-inferiority hypothesis
12
Investigational Device only in the US; Not available for sale in the US
EVEREST II Randomized Clinical Trial
Additional Analyses
Intention to Treat
 Safety
• Major Adverse Event Rate at 30 days
 Effectiveness
• Freedom from the combined outcome of death, MV surgery
>90 days or re-operation for valve dysfunction >90 days post
Index procedure, and MR >2+ at 12 months
Clinical Benefit (per protocol cohort)




MR Severity
Left Ventricular Function
NYHA Functional Class
Quality of Life (SF-36 Survey)
13
Investigational Device only in the US; Not available for sale in the US
EVEREST II RCT: Patient Flow
Per Protocol Cohort: Analysis of Device Performance
Randomized Cohort
n=279
Device Group
n=184
Randomized, not treated
Device, n=6
Control, n=15
Treated
n=178
Control Group
n=95
Treated
n=80
(86% MV repair)
Acute Procedural Success
Not Achieved
Acute Procedural Success
Achieved
Acute Procedural Success (APS)
= MR ≤2+ at discharge
30 days
30 days
99% Clinical Follow-up
99% Clinical Follow-up
12 months
12 months
98.5% Clinical Follow-up
98% Echo Follow-up
94% Clinical Follow-up
92% Echo Follow-up
n=41
n=137
n=136
n=134
n=79
Investigational Device only in the US; Not available for sale in the US
n=74
14
EVEREST II RCT: Patient Flow
Post MitraClip Procedure
Acute Procedural Success
Not Achieved
Acute Procedural Success
Achieved
n=137
n=41
No Additional
Intervention
n=11
2nd MitraClip
Procedure
n=2
MV Surgery Post
MitraClip Procedure
n=28
MV Surgery Post
MitraClip Procedure
n=9
2nd MitraClip
Procedure
n=3
n=37
81% Follow-up
96% MR ≤2+
at 12 months
15
Investigational Device only in the US; Not available for sale in the US
EVEREST II RCT: Patient Flow
Intention to Treat Cohort: Analysis of Treatment Strategy
Randomized Cohort
n=279
Device Group
n=184
Control Group
n=95
30 days
30 days
95% Follow-up
84% Follow-up
12 months
12 months
92% Follow-up
78% Follow-up
n=180
n=175
n=94
n=89
Patients randomized but not treated are included in ITT analysis
16
Investigational Device only in the US; Not available for sale in the US
EVEREST II RCT: Primary Endpoints
Per Protocol Cohort
Safety
Effectiveness
Major Adverse Events
Clinical Success Rate*
30 days
12 months
Device Group, n=136
Device Group, n=134
72.4%
9.6%
Control Group, n=79
pSUP <0.0001
Control Group, n=74
pNI =0.0012
57.0%
0
20
40
Met superiority hypothesis
• Pre-specified margin = 6%
• Observed difference = 47.4%
• 97.5% LCB = 34.4%
LCB = lower confidence bound
UCB = upper confidence bound
60
87.8%
0
20
40
60
80
100
Met non-inferiority hypothesis
• Pre-specified margin = 31%
• Observed difference = 15.4%
• 95% UCB = 25.4%
*
Freedom from the combined outcome of
death, MV surgery or re-operation for MV
dysfunction, MR >2+ at 12 months
Investigational Device only in the US; Not available for sale in the US
17
EVEREST II RCT: Primary Safety Endpoint
Per Protocol Cohort
30 Day MAE, non-hierarchical
Death
Major Stroke
Re-operation of Mitral Valve
Urgent / Emergent CV Surgery
Myocardial Infarction
Renal Failure
Deep Wound Infection
Ventilation >48 hrs
New Onset Permanent Atrial Fib
Septicemia
GI Complication Requiring Surgery
All Transfusions ≥2 units*
TOTAL % of Patients with MAE
*p<0.0001 if include Major Bleeding only
# Patients experiencing event
Device Group
(n=136)
0
0
0
0
0
0
0
0
0
0
1 (0.7%)
12 (8.8%)
9.6%
Control Group
(n=79)
2 (2.5%)
2 (2.5%)
1 (1.3%)
4 (5.1%)
0
0
0
4 (5.1%)
0
0
0
42 (53.2%)
57.0%
p<0.0001*
(95% CI 34.4%, 60.4%)
Investigational Device only in the US; Not available for sale in the US
18
Additional Analyses
 Intention to Treat Safety & Effectiveness
 Clinical Benefit (per protocol cohort)
•
•
•
•
MR Severity
Left Ventricular Function
NYHA Functional Class
Quality of Life
19
Investigational Device only in the US; Not available for sale in the US
EII RCT: Safety & Effectiveness Endpoints
Intention to Treat Cohort
Safety
Effectiveness
Major Adverse Events
Clinical Success Rate*
30 days
12 months
Device Group, n=180
Device Group, n=175
15.0%
Control Group, n=94
66.9%
pSUP <0.0001
Control Group, n=89
pNI =0.0005
47.9%
0
20
40
Met superiority hypothesis
• Pre-specified margin =2%
• Observed difference = 32.9%
• 97.5% LCB = 20.7%
LCB = lower confidence bound
UCB = upper confidence bound
60
74.2%
0
20
40
60
80
100
Met non-inferiority hypothesis
• Pre-specified margin = 25%
• Observed difference = 7.3%
• 95% UCB = 17.8%
*
Freedom from the combined outcome of death, MV
surgery or re-operation for MV dysfunction >90 days
post Index procedure, MR >2+ at 12 months
Investigational Device only in the US; Not available for sale in the US
20
EVEREST II RCT: MR Reduction
Per Protocol Cohort
Device Group
Control Group
100%
80%
≤2+
60%
≤2+
81.5%
3+/4+
97.0%
3+/4+
40%
20%
3+/4+
18.5%
0%
Baseline
n=137
12 Months
n=119
Baseline
n=80
12 Months
n=67
21
Investigational Device only in the US; Not available for sale in the US
EVEREST II RCT: MR Reduction
Per Protocol Cohort
100%
Device Group
Control Group
2+
2+
1+
80%
60%
3+/4+
40%
3+/4+
1+
0%
58.2%
18.4% (7/38)
Replacement
33.6%
20%
1+-2+
3+/4+
17.9%
36.1%
1+-2+ 11.8%
2+
0
7.7% (1/13)
Replacement
18.5%
2+
7.5%
13.4%
3.0%
Baseline
n=137
12 Months
n=119
Baseline
n=80
12 Months
n=67
22
Investigational Device only in the US; Not available for sale in the US
EVEREST II RCT: Left Ventricular Volume
Per Protocol Cohort
200
Device Group
n=118, matched data
200
p<0.0001
p<0.0001
160
120
p=0.0005
80
Volume (ml)
Volume (ml)
160
Control Group
n=65, matched data
120
40
40
0
0
LVEDV
LVESV
Baseline
p=0.0255
80
LVEDV
LVESV
12 Months
LVEDV = left ventricular end diastolic volume
LVESV = left ventricular end systolic volume
Pre-specified hypothesis
Investigational Device only in the US; Not available for sale in the US
for statistical analysis 23
EVEREST II RCT: Left Ventricular Dimension
Per Protocol Cohort
Control Group
n=65, matched data
Device Group
n=118, matched data
6
p<0.0001
6
5
p=0.0564
4
3
2
Dimension (cm)
5
Dimension (cm)
p<0.0001
4
3
2
1
1
0
0
LVID diastole
LVID systole
Baseline
p=0.4785
LVID diastole
LVID systole
12 Months
LVIDd = left ventricular internal diameter, diastole
Pre-specified hypothesis
LVIDs = left ventricular internal diameter, systole
Investigational Device only in the US; Not available for sale in the US
for statistical analysis 24
EVEREST II RCT: NYHA Functional Class
Per Protocol Cohort
100
Device Group
Control Group
p<0.0001
p<0.0001
I
Percent Patients
I
80
II
I
60
40
0
97.6%
NYHA
Class I/II
I
87.9%
NYHA
Class I/II
III
III
20
II
II
II
IV
IV
Baseline 12 months
n=124, Matched data
III
Baseline 12 months
n=66, Matched data
Hypothesis not pre-specified for statistical analysis
Investigational Device only in the US; Not available for sale in the US
25
Score
EVEREST II RCT: Quality of Life, SF-36 Survey
Per Protocol Cohort
30 Day Scores
60
50
Device Group
12 Month Scores
Control Group
p<0.0001
P=0.2910
p<0.0001
P=0.0043
60
50
40
40
30
30
20
20
10
10
0
0
PCS
MCS
n=120, matched pairs
PCS
MCS
n=64, matched pairs
Baseline
PSC = Physical Component Summary
MCS = Mental Component Summary
30 days
Device Group
Control Group
P<0.0001
P<0.0001
PCS
P=0.0057
P=0.0017
MCS
n=110, matched pairs
PCS
MCS
n=60, matched pairs
12 Months
Hypothesis not pre-specified for statistical analysis 26
Investigational Device only in the US; Not available for sale in the US
EVEREST II RCT: Summary
 Safety & effectiveness endpoints met
• Safety: MAE rate at 30 days
– MitraClip device patients: 9.6%
– MV surgery patients: 57%
• Effectiveness: Clinical Success Rate at 12 months
– MitraClip device patients: 72%
– MV Surgery patients: 88%
 Clinical benefit demonstrated for MitraClip System and MV surgery
patients through 12 months
– Improved LV function
– Improved NYHA Functional Class
– Improved Quality of Life
 Surgery remains an option after the MitraClip procedure
27
Investigational Device only in the US; Not available for sale in the US
EVEREST II RCT: Conclusion
The MitraClip procedure is an important
therapeutic option for selected patients
with significant mitral regurgitation given
the demonstrated safety, effectiveness
and clinical benefit.
28
Investigational Device only in the US; Not available for sale in the US